REVErsing Airway Remodelling With Tezepelumab | NCT05651841

NCT05651841

Protocol Section

Identification Module

Results Section

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Annotation Section

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Document Section

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Derived Section

Miscellaneous Info Module

Status Module

Description Module

Detailed Description

Tezepelumab is a human IgG2l monoclonal antibody (mAb) directed against TSLP. Double-blind, randomized controlled trials comparing Tezepelumab treatment against placebo demonstrate net positive benefits in asthma patients. Animal research currently indicates that blocking TSLP can prevent bronchial remodelling in murine models (Chen et al. 2013), but no such observations have been attempted in humans. Within this context, the aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures.

The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles.

The primary objective of this protocol is therefore to compare the change-from-baseline in the average percentage bronchial wall area (%WA = (wall area (mm2)/ (wall area (mm2) + lumen area (mm2)))×100) for patients with asthma and undergoing 6 months of tezepelumab treatment with a similar population treated via placebo. Secondarily, continued treatment effects associated with longer treatment (12 months) or remanence after treatment stopping at 6 months will also be quantified. Study arms will additionally be compared in terms of:

Changes in radiomics (CT-scan data);
Changes in exacerbation rates and lung function;
Changes in serum club cell secretory protein (CCSP);
Changes in nasal single-cell transcriptomic signatures.

This study also has an exploratory component designed to characterize the physiological repair environment. In depth radiomic and transcriptomic (including single-cell analyses) profiling will be performed. Finally, the capacity of baseline data to predict the response to tezepelumab will also be explored.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo / Tezepelumab	Experimental	After 6-months of treatment, patients initially receiving placebo will switch to Tezepelumab for an additional 6 months. For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks. Each subcutaneous injection corresponds to 210 mg of Tezepelumab or analogous placebo.	Drug: Tezepelumab Other: placebo
Tezepelumab / Tezepelumab	Experimental	After 6-months of treatment, patients receiving Tezepelumab will continue Tezepelumab for an additional 6 months. For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks.Each subcutaneous injection corresponds to 210 mg of Tezepelumab.	Drug: Tezepelumab
Tezepelumab / Placebo	Experimental	After 6-months of treatment, patients receiving Tezepelumab will be switched to a placebo for an additional 6 months. For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks. Each subcutaneous injection corresponds to 210 mg of Tezepelumab or analogous placebo.	Drug: Tezepelumab Other: placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Tezepelumab	Drug	Tezepelumab is supplied as a sterile, single-use, preservation-free, clear, colourless to slightly yellow liquid for subcutaneous administration in accessorized pre-filled syringes (APFS). Injections will be performed by study staff (doctors or nurses) during face-to-face study visits in participating centres. Subcutaneous injections are performed in a different body-part following the suggested rotation diagram.

Measure	Description	Time Frame
Comparaison on CT-scan in the change in mean percentage bronchial wall area (%WA) at the B1 and B8 bronchi, generations 3, 4 and 5	%WA = (wall area (mm²)/ (wall area (mm²) + lumen area (mm²)))×100) at bronchial levels likely to be affected.	Between baseline and 6 months

Measure	Description	Time Frame
compare on CT-scan the change in mean %WA between arms	%WA = (wall area (mm2)/ (wall area (mm2) + lumen area (mm2)))×100) at bronchial levels likely to be affected.	Between baseline and 12 months
Comparaison on CT-scan in the average percentage bronchia wall thickness index (%WT) at the B1 and B8 bronchi, generations 3, 4 and 5

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Admitted to screening visit:

Minimum age: 18
Maximum age: 85
Able to perform an inspiratory and expiratory thoracic computed tomography (CT) scan, plus a nasal CT
In stable condition for CT scan
Physician-diagnosed asthma according to GINA criteria
Disease with clinical impact: at least 1 severe or 2 moderate exacerbations in the previous 12 months despite treatment according to the best standards of care
Maximal inhaled therapy comprising high dose ICS and at least a second controller according to GINA

Based on results of screening visit and run-in:

Post-bronchodilator forced expiratory volume in 1 second (FEV1) predicted values must be at 25-90%
Asthma Control Questionnaire 6 (ACQ6) > 1.5
Oral corticosteroid maintenance therapy (if used) ≤7.5 mg/day
On CT scan, the average percentage wall area index at the B1 and B8 bronchi (generation 3, 4, 5) is >65%

Exclusion Criteria:

CT abnormalities evocative of any respiratory condition other than asthma
Treatment regimen discordant with best practices
Pulmonary disease other than asthma requiring treatment during the previous 12 months
A smoking history of >20 pack years
Receipt of any marketed or investigational biologic agent§ within 3 months or 5 halflives (whichever is longer) prior to randomization or receipt of any investigational non biologic agent within 30 days or 5 half-lives (whichever is longest) prior to randomization or receipt of live attenuated vaccines 30 days prior to the date of randomization. Participants enrolled in current or previous tezepelumab studies will not be included. Participants on previous biologics treatment are allowed to enter the study provided the appropriate washout period is fulfilled.
Absence of signed consent
Non-beneficiary of the French social security, single-payer health insurance system
Presence of any condition (physical, psychological or other) that might, in the investigator's opinion, hinder study performance
The patient is unavailable or unwilling to participate in future visits
Potential interference from other studies
Protected populations according to the French public health code
Male or female patients seeking to conceive a child
Women of childbearing potential and fertile men not using birth control method
Pregnant, breastfeeding or lactating women
History of a clinically significant infection, including upper (URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral medications finalised < 2 weeks before randomization. Patients with preexisting serious infections should be treated before initiating therapy with tezepelumab.
A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy.
Patients using vaping products, including electronic cigarettes (because may induce abnormality at CT scan).
Bronchial thermoplasty in the last 12 months prior to Visit 1.
History of documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy.
History of known immunodeficiency disorder including a positive human immunodeficiency virus test or the participant taking antiretroviral medications as determined by medical history and/or participant's verbal report.
Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior to randomization.
Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate, cyclosporine, etc.), except for OCS used in the treatment of asthma/asthma exacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) prior to randomization.
Receipt of immunoglobulin or blood products within 30 days prior to randomization.
Receipt of allergen immunotherapy not stable within 30 days prior to randomization or with anticipated change during the treatment period.

Facility	Status	City	State	ZIP	Country	Contacts
CHU Dijon		Dijon			France
CHU Grenoble Alpes La Tronche

ID	Term
D056151	Airway Remodeling
D001249	Asthma

ID	Term
D020763	Pathological Conditions, Anatomical
D013568	Pathological Conditions, Signs and Symptoms
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases